Activation of the p38 MAPK signaling cascade is associated with cellular response to cytokines, irradiation, and oxidants. In peripheral neurons, hyperglycemia-induced activation of p38 MAPK pathway is associated with reduced motor nerve conduction velocity and apoptosis. We hypothesize that hyperglycemia induces oxidative stress and is associated with reduced axonal transport rates in the CNS. We also hypothesize that hyperglycemia-induced oxidative stress activates the p38 MAPK pathway in association with phosphorylation of tau protein leading to axonal transport deficits in CNS neurons. Last, we hypothesize that reduction of oxidative stress through the overexpression of SOD2 should ameliorate these effects. To address these hypotheses, we utilized a dynamic, in vivo, MRI methodology, MEMRI, to measure axonal transport rates noninvasively. Manganese ion is a paramagnetic MRI contrast agent that instills positive contrast in spin-lattice weighted MRI images. Additionally, Mn2+ is known to enter the cells via voltage-gated calcium channels. Once in the cells, Mn2+ is packaged into vesicles and transported along microtubules via fast axonal transport and released at the synapse. The rates of Mn2+ transported along the axons are reflective of the fast axonal transport rates. Dynamic T1-weighted MEMRI enables trans-synaptic, in vivo, MRI detectable neuronal tract tracing to map neuronal pathways. Overexpression of SOD2 reduces superoxide load in DRG neurons and in hippocampal neurons and prevents cellular injury. The SOD2 overexpressing mice are a transgenic line that overexpress human SOD2 gene driven by the b-actin promoter. We first determined axonal transport rates in STZ-treated wildtype and SOD2 overexpressing mice. We next determined the levels of ROS in the different groups of mice. Last, we determined the protein and gene expression levels of p38 MAPK and tau. Our findings suggest that hyperglycemia-induced oxidative stress instills axonal transport deficits in ORNs through the phosphorylation of p38 MAPK and tau. The effects of hyperglycemia on the CNS remain poorly understood. Our results indicate that MEMRI noninvasively depicts significant reduction of axonal transport rates in WT-STZ mice during hyperglycemia. We also determined that the axonal transport rate deficits are associated with activation of p38 MAPK signaling cascade and tau phosphorylation in hyperglycemic mice at 1-week. Wseveral reports indicated that calcium homeostasis is disturbed with increased levels of intracellular calcium in several cells during long-term diabetes and increase in T-type calcium currents in peripheral neurons following two weeks of hyperglycemia, 5-12 days of hyperglycemia does not cause remarkable alterations in calcium homeostasis. Upon SOD2 overexpression, the deficits in axonal transport recovered in association with kinase inhibitors restoration of levels of phosphorylated p38 MAPK and tau protein. Because SOD2 is exclusively localized to the mitochondria of SOD2 transgenic mice.